DESCRIPTION(Adapted from applicant's abstract): Exercise has been associated with enhanced cognitive function as well as maintenance of cognitive health. The molecular mechanisms that may underlie this improved brain functioning, however, are only beginning to be identified. Brain-derived neurotrophic factor (BDNF) has been demonstrated to enhance the survival of cortical neurons, promote their recovery after damage, and participate in use-dependent plasticity mechanisms such as long-term potentiation and learning. Thus, BDNF regulation is critical to brain functions. We have demonstrated that exercise (voluntary running) can increase the expression of multiple BDNF transcript forms in rat brain. This effect is rapid (occurring within hours of exercise onset) and is sustained. This effect is regionally selective and is particularly prominent in the hippocampus, a brain region not normally associated with motor activity. A large literature suggests that such trophic factor responses are regulated by many other variables, including specific neurotransmitter and hormone interactions. Recently, a cAMP-response element (CRE) has been identified on the exon III BDNF promoter. The CRE is active in constructs, which suggests the hypothesis that CRE-binding protein (CREB) and the regulation of CREB activity may serve as a convergence point for the regulation of induction of the exon Ill-containing BDNF transcript (exon III-BDNF). Various neurotransmitters, activation of voltage sensitive calcium channels and the hormone estrogen may converge on the regulation of CREB activity and thereby on exon 111BDNF mRNA expression. Exon l-BDNF expression may be regulated by neurotransmitters, estrogen and corticosteroids. Specific studies will be directed toward exploring the role of the NMDA receptor, cholinergic and moluminergic "stems on BDNF expression, because initial evidence suggests that they can modulate BDNF -ion. F," cholinergic and monaminergic systems also appear to modulate cognitive function and behaviaral state. In addition to studies on mechanism, parallel studies will be conducted on the age-dependency, regional specificity, and means to enhance BDNF expression by combined behavioral and pharmacological interventions. Data from the proposed experiments will provide an initial characterization of how a simple, widely practiced activity-exercise-regulates expression of BDNF, a molecule increasingly recognized for its critical role in brain function.